tbuckley/cabot-search huggingface dataset:
Missense mutations in <i>PIEZO1,</i> which encodes the Piezo1 mechanosensor protein, define Er red blood cell antigens
Authors: Vanja Karamatic Crew, Louise A. Tilley, Timothy J. Satchwell, Samah A. AlSubhi, Benjamin Jones, Frances A. Spring, Piers J. Walser, Catarina Martins Freire, Nicoletta Murciano, Maria Giustina Rotordam, Svenja J. Woestmann, Marwa Hamed, Reem Alradwan, Mouza AlKhrousey, Ian Skidmore, Sarah Lewis, Shimon Hussain, Jane Jackson, Tom Latham, Mark D. Kilby, William Lester, Nadine Becker, Markus Rapedius, Ashley M. Toye, Nicole M. Thornton
Journal: Blood (2022)

Despite the identification of the high-incidence red cell antigen Era nearly 40 years ago, the molecular background of this antigen, together with the other 2 members of the Er blood group collection, has yet to be elucidated. Whole exome and Sanger sequencing of individuals with serologically defined Er alloantibodies identified several missense mutations within the PIEZO1 gene, encoding amino acid substitutions within the extracellular domain of the Piezo1 mechanosensor ion channel. Confirmation of Piezo1 as the carrier molecule for the Er blood group antigens was demonstrated using immunoprecipitation, CRISPR/Cas9-mediated gene knockout, and expression studies in an erythroblast cell line. We report the molecular bases of 5 Er blood group antigens: the recognized Era, Erb, and Er3 antigens and 2 novel high-incidence Er antigens, described here as Er4 and Er5, establishing a new blood group system. Anti-Er4 and anti-Er5 are implicated in severe hemolytic disease of the fetus and newborn. Demonstration of Piezo1, present at just a few hundred copies on the surface of the red blood cell, as the site of a new blood group system highlights the potential antigenicity of even low-abundance membrane proteins and contributes to our understanding of the in vivo characteristics of this important and widely studied protein in transfusion biology and beyond.
Implications of <scp>RAS</scp> mutational status in subsets of patients with newly diagnosed acute myeloid leukemia across therapy subtypes
Authors: Daniel Rivera, Kunhwa Kim, Rashmi Kanagal‐Shamanna, Gautam Borthakur, Guillermo Montalban‐Bravo, Naval Daver, Courtney Dinardo, Nicholas J. Short, Musa Yilmaz, Naveen Pemmaraju, Koichi Takahashi, Elias J. Jabbour, Sherry Pierce, Marina Konopleva, Kapil Bhalla, Guillermo Garcia‐Manero, Farhad Ravandi, Hagop Kantarjian, Tapan M. Kadia
Journal: American Journal of Hematology (2022)

Activating mutations in RAS have been reported in about 10-15% of patients with AML; previous studies have not identified a prognostic significance. However, RAS mutations have emerged as a potential resistance mechanism to treatment with inhibitors of FLT3, IDH, and BCL2. We aimed to determine the characteristics and outcomes of patients with RAS-mutated (RAS-mut) AML across therapy subsets of 1410 patients newly diagnosed (ND AML). RAS-mut was observed in 273 (20%) patients. Overall, patients with RAS-mut AML had an estimated 3-year survival rate of 38% vs. 28% in those with RAS wild type (RAS-wt), p = .01. Among patients with RAS-mut, favorable karyotype and concomitant NPM1 mutations were associated with a higher CR/CRi rate, OR 23.2 (95% CI: 2.7-192.7; p < .001) and OR 2.8 (95% CI: 1.1-6.9; p = .02), respectively, while secondary and treated secondary (ts)-AML were associated with low response rates, OR 0.34 (95% CI: 0.1-0.9; p = .04) and OR 0.22 (95% CI: 0.09-0.5; p = .001), respectively. Intensive chemotherapy was associated with high response rates OR 5.9 (95% CI: 2.9-12.2; p < .001). Better median OS was observed among those with favorable karyotype, HR 0.28 (95% CI: 0.1-0.6; p = .002), and those treated with intensive chemotherapy, HR 0.42 (95% CI: 0.2-0.6 p < .001). Conversely, ts- AML and co-occurrence of mutations in TP53 were associated with poor median OS; HR 2.3 (95% CI: 1.4-3.9; p = .001) and HR 1.7 (95% CI: 0.9-3.1; p = .06), respectively. The addition of venetoclax was associated with a non-significant improvement in CR/CRi and OS.
Cell‐Derived Vesicles for Nanoparticles' Coating: Biomimetic Approaches for Enhanced Blood Circulation and Cancer Therapy
Authors: Carolina F. Rodrigues, Natanael Fernandes, Duarte de Melo‐Diogo, Ilídio J. Correia, André F. Moreira
Journal: Advanced Healthcare Materials (2022)

Cancer nanomedicines are designed to encapsulate different therapeutic agents, prevent their premature release, and deliver them specifically to cancer cells, due to their ability to preferentially accumulate in tumor tissue. However, after intravenous administration, nanoparticles immediately interact with biological components that facilitate their recognition by the immune system, being rapidly removed from circulation. Reports show that less than 1% of the administered nanoparticles effectively reach the tumor site. This suboptimal pharmacokinetic profile is pointed out as one of the main factors for the nanoparticles' suboptimal therapeutic effectiveness and poor translation to the clinic. Therefore, an extended blood circulation time may be crucial to increase the nanoparticles' chances of being accumulated in the tumor and promote a site-specific delivery of therapeutic agents. For that purpose, the understanding of the forces that govern the nanoparticles' interaction with biological components and the impact of the physicochemical properties on the in vivo fate will allow the development of novel and more effective nanomedicines. Therefore, in this review, the nano-bio interactions are summarized. Moreover, the application of cell-derived vesicles for extending the blood circulation time and tumor accumulation is reviewed, focusing on the advantages and shortcomings of each cell source.
Remote control of the recruitment and capture of endogenous stem cells by ultrasound for in situ repair of bone defects
Authors: Yanni He, Fei Li, Peng Jiang, Feiyan Cai, Qin Lin, Meijun Zhou, Hongmei Liu, Fei Yan
Journal: Bioactive Materials (2022)

Stem cell-based tissue engineering has provided a promising platform for repairing of bone defects. However, the use of exogenous bone marrow mesenchymal stem cells (BMSCs) still faces many challenges such as limited sources and potential risks. It is important to develop new approach to effectively recruit endogenous BMSCs and capture them for in situ bone regeneration. Here, we designed an acoustically responsive scaffold (ARS) and embedded it into SDF-1/BMP-2 loaded hydrogel to obtain biomimetic hydrogel scaffold complexes (BSC). The SDF-1/BMP-2 cytokines can be released on demand from the BSC implanted into the defected bone via pulsed ultrasound (p-US) irradiation at optimized acoustic parameters, recruiting the endogenous BMSCs to the bone defected or BSC site. Accompanied by the daily p-US irradiation for 14 days, the alginate hydrogel was degraded, resulting in the exposure of ARS to these recruited host stem cells. Then another set of sinusoidal continuous wave ultrasound (s-US) irradiation was applied to excite the ARS intrinsic resonance, forming highly localized acoustic field around its surface and generating enhanced acoustic trapping force, by which these recruited endogenous stem cells would be captured on the scaffold, greatly promoting them to adhesively grow for in situ bone tissue regeneration. Our study provides a novel and effective strategy for in situ bone defect repairing through acoustically manipulating endogenous BMSCs.
CYP1B1-derived epoxides modulate the TRPA1 channel in chronic pain
Authors: Lili Sun, Jie Zhang, Changshan Niu, Cassandra E. Deering-Rice, Ronald W. Hughen, John G. Lamb, Katherine Rose, Kevin M. Chase, Marysol Almestica-Roberts, Markel Walter, Eric W. Schmidt, Alan R. Light, Baldomero M. Olivera, Christopher A. Reilly
Journal: Acta Pharmaceutica Sinica B (2022)

Pain is often debilitating, and current treatments are neither universally efficacious nor without risks. Transient receptor potential (TRP) ion channels offer alternative targets for pain relief, but little is known about the regulation or identities of endogenous TRP ligands that affect inflammation and pain. Here, transcriptomic and targeted lipidomic analysis of damaged tissue from the mouse spinal nerve ligation (SNL)-induced chronic pain model revealed a time-dependent increase in Cyp1b1 mRNA and a concurrent accumulation of 8,9-epoxyeicosatrienoic acid (EET) and 19,20-EpDPA post injury. Production of 8,9-EET and 19,20-EpDPA by human/mouse CYP1B1 was confirmed in vitro, and 8,9-EET and 19,20-EpDPA selectively and dose-dependently sensitized and activated TRPA1 in overexpressing HEK-293 cells and Trpa1-expressing/AITC-responsive cultured mouse peptidergic dorsal root ganglia (DRG) neurons. TRPA1 activation by 8,9-EET and 19,20-EpDPA was attenuated by the antagonist A967079, and mouse TRPA1 was more responsive to 8,9-EET and 19,20-EpDPA than human TRPA1. This latter effect mapped to residues Y933, G939, and S921 of TRPA1. Intra-plantar injection of 19,20-EpDPA induced acute mechanical, but not thermal hypersensitivity in mice, which was also blocked by A967079. Similarly, Cyp1b1-knockout mice displayed a reduced chronic pain phenotype following SNL injury. These data suggest that manipulation of the CYP1B1-oxylipin-TRPA1 axis might have therapeutic benefit.
An anti-bacterial porous shape memory self-adaptive stiffened polymer for alveolar bone regeneration after tooth extraction
Authors: Weijun Zhang, Meilin Yu, Yongqiang Cao, Zihan Zhuang, Kunxi Zhang, Dong Chen, Wenguang Liu, Jingbo Yin
Journal: Bioactive Materials (2022)

The regeneration of alveolar bone after tooth extraction is critical for the placement of dental implants. Developing a rigid porous scaffold with defect shape adaptability is of great importance but challenging for alveolar bone regeneration. Herein, we design and synthesize a biocompatible poly(l-glutamic acid)-g-poly(ε-caprolactone) (PLGA-g-PCL) porous shape memory (SM) polymer. The PLGA-g-PCL is then copolymerized with acryloyl chloride grafted poly(ω-pentadecalactone) (PPDLDA) having a higher phase transition temperature than shape recovery temperature to maintain stiffness after shape recovery to resist chewing force. The hybrid polydopamine/silver/hydroxyapatite (PDA/Ag/HA) is coated to the surface of (PLGA-g-PCL)-PPDL scaffold to afford the anti-bacterial activity. The porous SM scaffold can be deformed into a compact size and administered into the socket cavity in a minimally invasive mode, and recover its original shape with a high stiffness at body temperature, fitting well in the socket defect. The SM scaffold exhibits robust antibacterial activity against Staphylococcus aureus (S. aureus). The porous microstructure and cytocompatibility of PLGA allow for the ingrowth and proliferation of stem cells, thus facilitating osteogenic differentiation. The micro-CT and histological analyses demonstrate that the scaffold boosts efficient new bone regeneration in the socket of rabbit mandibular first premolar. This porous shape memory self-adaptive stiffened polymer opens up a new avenue for alveolar bone regeneration.
The role of phosphatidylcholine 34:1 in the occurrence, development and treatment of ulcerative colitis
Authors: Tengjie Yu, Zhihao Zhou, Shijia Liu, Changjian Li, Zhi-Wei Zhang, Yong Zhang, Wei Jin, Keanqi Liu, Shuying Mao, Lei Zhu, Lin Xie, Guangji Wang, Yan Liang
Journal: Acta Pharmaceutica Sinica B (2022)

Lipid homeostasis is considered to be related to intestinal metabolic balance, while its role in the pathogenesis and treatment of ulcerative colitis (UC) remains largely unexplored. The present study aimed to identify the target lipids related to the occurrence, development and treatment of UC by comparing the lipidomics of UC patients, mice and colonic organoids with the corresponding healthy controls. Here, multi-dimensional lipidomics based on LC-QTOF/MS, LC-MS/MS and iMScope systems were constructed and used to decipher the alteration of lipidomic profiles. The results indicated that UC patients and mice were often accompanied by dysregulation of lipid homeostasis, in which triglycerides and phosphatidylcholines were significantly reduced. Notably, phosphatidylcholine 34:1 (PC34:1) was characterized by high abundance and closely correlation with UC disease. Our results also revealed that down-regulation of PC synthase PCYT1α and Pemt caused by UC modeling was the main factor leading to the reduction of PC34:1, and exogenous PC34:1 could greatly enhance the fumarate level via inhibiting the transformation of glutamate to N-acetylglutamate, thus exerting an anti-UC effect. Collectively, our study not only supplies common technologies and strategies for exploring lipid metabolism in mammals, but also provides opportunities for the discovery of therapeutic agents and biomarkers of UC.
Amino porphyrin-peptide assemblies induce ribosome damage and cancer stem cell inhibition for an enhanced photodynamic therapy
Authors: Jian Wang, Baochan Yang, Chaofan Lv, Tiancheng Chen, Lixin Sun, Lei Sun, Junfeng Hao, Fang Ding, Tianyu Wang, Jianzhuang Jiang, Yan Qin
Journal: Biomaterials (2022)
Effectiveness and Safety of Colonic and Capsule Fecal Microbiota Transplantation for Recurrent Clostridioides difficile Infection
Authors: Byron P. Vaughn, Monika Fischer, Colleen R. Kelly, Jessica R. Allegretti, Carolyn Graiziger, Juana Thomas, Emma McClure, Amanda J. Kabage, Alexander Khoruts
Journal: Clinical Gastroenterology and Hepatology (2022)
Micropeptide MIAC inhibits the tumor progression by interacting with AQP2 and inhibiting EREG/EGFR signaling in renal cell carcinoma
Authors: Mengwei Li, Guangxiang Liu, Xinrong Jin, Hongqian Guo, Sarra Setrerrahmane, Xindi Xu, Tiantian Li, Yunfei Lin, Hanmei Xu
Journal: Molecular Cancer (2022)

Abstract Background Although, micropeptides encoded by non-coding RNA have been shown to have an important role in a variety of tumors processes, there have been no reports on micropeptide in renal cell carcinoma (RCC). Based on the micropeptide MIAC (micropeptide inhibiting actin cytoskeleton) discovered and named in the previous work, this study screened its tumor spectrum, and explored its mechanism of action and potential diagnosis and treatment value in the occurrence and development of renal carcinoma. Methods The clinical significance of MIAC in RCC was explored by bioinformatics analysis through high-throughput RNA-seq data from 530 patients with kidney renal clear cell carcinoma (KIRC) in the TCGA database, and the detection of clinical samples of 70 cases of kidney cancer. In vitro and in vivo experiments to determine the role of MIAC in renal carcinoma cell growth and metastasis; High-throughput transcriptomics, western blotting, immunoprecipitation, molecular docking, affinity experiments, and Streptavidin pulldown experiments identify MIAC direct binding protein and key regulatory pathways. Results The analysis of 600 renal carcinoma samples from different sources revealed that the expression level of MIAC is significantly decreased, and corelated with the prognosis and clinical stage of tumors in patients with renal carcinoma. Overexpression of MIAC in renal carcinoma cells can significantly inhibit the proliferation and migration ability, promote apoptosis of renal carcinoma cells, and affect the distribution of cells at various stages. After knocking down MIAC, the trend is reversed. In vivo experiments have found that MIAC overexpression inhibit the growth and metastasis of RCC, while the synthetized MIAC peptides can significantly inhibit the occurrence and development of RCC in vitro and in vivo. Further mechanistic studies have demonstrated that MIAC directly bind to AQP2 protein, inhibit EREG/EGFR expression and activate downstream pathways PI3K/AKT and MAPK to achieve anti-tumor effects. Conclusions This study revealed for the first time the tumor suppressor potential of the lncRNA-encoded micropeptide MIAC in RCC, which inhibits the activation of the EREG/EGFR signaling pathway by direct binding to AQP2 protein, thereby inhibiting renal carcinoma progression and metastasis. This result emphasizes that the micropeptide MIAC can provide a new strategy for the diagnosis and treatment of RCC.
Physician Wellness in Academic Cardiovascular Medicine: A Scientific Statement From the American Heart Association
Authors: Elisa A. Bradley, David Winchester, Carlos E. Alfonso, Andrea J. Carpenter, Meryl S. Cohen, Dawn M. Coleman, Miriam Jacob, Hani Jneid, Miguel A. Leal, Zainab Mahmoud, Laxmi S. Mehta, Chittur A. Sivaram
Journal: Circulation (2022)

Academic medicine as a practice model provides unique benefits to society. Clinical care remains an important part of the academic mission; however, equally important are the educational and research missions. More specifically, the sustainability of health care in the United States relies on an educated and expertly trained physician workforce directly provided by academic medicine models. Similarly, the research charge to deliver innovation and discovery to improve health care and to cure disease is key to academic missions. Therefore, to support and promote the growth and sustainability of academic medicine, attracting and engaging top talent from fellows in training and early career faculty is of vital importance. However, as the health care needs of the nation have risen, clinicians have experienced unprecedented demand, and individual wellness and burnout have been examined more closely. Here, we provide a close look at the unique drivers of burnout in academic cardiovascular medicine and propose system-level and personal interventions to support individual wellness in this model.
African Ancestry–Associated Gene Expression Profiles in Triple-Negative Breast Cancer Underlie Altered Tumor Biology and Clinical Outcome in Women of African Descent
Authors: Rachel Martini, Princesca Delpe, Timothy R. Chu, Kanika Arora, Brittany Lord, Akanksha Verma, Deepa Bedi, Balasubramanyam Karanam, Isra Elhussin, Yalei Chen, Endale Gebregzabher, Joseph K. Oppong, Ernest K. Adjei, Aisha Jibril Suleiman, Baffour Awuah, Mahteme Bekele Muleta, Engida Abebe, Ishmael Kyei, Frances S. Aitpillah, Michael O. Adinku, Kwasi Ankomah, Ernest Baawuah Osei-Bonsu, Dhananjay A. Chitale, Jessica M. Bensenhaver, David S. Nathanson, LaToya Jackson, Lindsay F. Petersen, Erica Proctor, Brian Stonaker, Kofi K. Gyan, Lee D. Gibbs, Zarko Monojlovic, Rick A. Kittles, Jason White, Clayton C. Yates, Upender Manne, Kevin Gardner, Nigel Mongan, Esther Cheng, Paula Ginter, Syed Hoda, Olivier Elemento, Nicolas Robine, Andrea Sboner, John D. Carpten, Lisa Newman, Melissa B. Davis
Journal: Cancer Discovery (2022)

Women of sub-Saharan African descent have disproportionately higher incidence of triple-negative breast cancer (TNBC) and TNBC-specific mortality across all populations. Population studies show racial differences in TNBC biology, including higher prevalence of basal-like and quadruple-negative subtypes in African Americans (AA). However, previous investigations relied on self-reported race (SRR) of primarily U.S. populations. Due to heterogeneous genetic admixture and biological consequences of social determinants, the true association of African ancestry with TNBC biology is unclear. To address this, we conducted RNA sequencing on an international cohort of AAs, as well as West and East Africans with TNBC. Using comprehensive genetic ancestry estimation in this African-enriched cohort, we found expression of 613 genes associated with African ancestry and 2,000+ associated with regional African ancestry. A subset of African-associated genes also showed differences in normal breast tissue. Pathway enrichment and deconvolution of tumor cellular composition revealed that tumor-associated immunologic profiles are distinct in patients of African descent.
Intestinal epithelial c-Maf expression determines enterocyte differentiation and nutrient uptake in mice
Authors: Catalina Cosovanu, Philipp Resch, Stefan Jordan, Andrea Lehmann, Markus Ralser, Vadim Farztdinov, Joachim Spranger, Michael Mülleder, Sebastian Brachs, Christian Neumann
Journal: The Journal of Experimental Medicine (2022)

The primary function of the small intestine (SI) is to absorb nutrients to maintain whole-body energy homeostasis. Enterocytes are the major epithelial cell type facilitating nutrient sensing and uptake. However, the molecular regulators governing enterocytes have remained undefined. Here, we identify c-Maf as an enterocyte-specific transcription factor within the SI epithelium. c-Maf expression was determined by opposing Noggin/BMP signals and overlapped with the zonated enrichment of nutrient transporters in the mid-villus region. Functionally, enterocytes required c-Maf to appropriately differentiate along the villus axis. Specifically, gene programs controlling carbohydrate and protein absorption were c-Maf-dependent. Consequently, epithelial cell-specific c-Maf deletion resulted in impaired enterocyte maturation and nutrient uptake, including defects in the adaptation to different nutrient availability. Concomitantly, intraepithelial lymphocytes were less abundant, while commensal epithelial cell-attaching SFB overgrew in a c-Maf-deficient environment, highlighting the close interdependence between the intestinal epithelium, immune system, and microbiota. Collectively, our data identified c-Maf as a key regulator of SI enterocyte differentiation and function, essential for nutrient, immune, and microbial homeostasis.
Association of Early Oseltamivir With Improved Outcomes in Hospitalized Children With Influenza, 2007-2020
Authors: Patrick S. Walsh, David Schnadower, Yin Zhang, Sriram Ramgopal, Samir S. Shah, Paria M. Wilson
Journal: JAMA Pediatrics (2022)

Oseltamivir is recommended for all children hospitalized with influenza, despite limited evidence supporting its use in the inpatient setting.To determine whether early oseltamivir use is associated with improved outcomes in children hospitalized with influenza.This multicenter retrospective study included 55 799 children younger than 18 years who were hospitalized with influenza from October 1, 2007, to March 31, 2020, in 36 tertiary care pediatric hospitals who participate in the Pediatric Health Information System database. Data were analyzed from January 2021 to March 2022.Early oseltamivir treatment, defined as use of oseltamivir on hospital day 0 or 1.The primary outcome was hospital length of stay (LOS) in calendar days. Secondary outcomes included 7-day hospital readmission, late (hospital day 2 or later) intensive care unit (ICU) transfer, and a composite outcome of in-hospital death or use of extracorporeal membrane oxygenation (ECMO). Inverse probability treatment weighting (IPTW) based on propensity scoring was used to address confounding by indication. Mixed-effects models were used to compare outcomes between children who did and did not receive early oseltamivir treatment. Outcomes were also compared within high-risk subgroups based on age, presence of a complex chronic condition, early critical illness, and history of asthma.The analysis included 55 799 encounters from 36 hospitals. The median (IQR) age of the cohort was 3.61 years (1.03-8.27); 56% were male, and 44% were female. A total of 33 207 patients (59.5%) received early oseltamivir. In propensity score-weighted models, we found that children treated with early oseltamivir had shorter LOS (median 3 vs 4 days; IPTW model ratio, 0.52; 95% CI, 0.52-0.53) and lower odds of all-cause 7-day hospital readmission (3.5% vs 4.8%; adjusted odds ratio [aOR], 0.72; 95% CI, 0.66-0.77), late ICU transfer (2.4% vs 5.5%; aOR, 0.41; 95% CI, 0.37-0.46), and the composite outcome of death or ECMO use (0.9% vs 1.4%; aOR, 0.63; 95% CI, 0.54-0.73).Early use of oseltamivir in hospitalized children was associated with shorter hospital stay and lower odds of 7-day readmission, ICU transfer, ECMO use, and death. These findings support the current recommendations for oseltamivir use in children hospitalized with influenza.